Summary of work: The neuroanatomic and neurophysiologic underpinnings of age-associated cognitive and memory change remain unclear, as there are a limited number of studies of longitudinal brain changes in individuals without dementia. We are performing serial magnetic resonance imaging (MRI), positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's Disease (AD). An understanding of these associations and early detection of brain changes will be critical in identifying individuals likely to benefit from new interventions. Since 2005, we also have acquired 11-C-PIB PET imaging studies of amyloid distribution in the brain to enhance the identification of preclinical AD. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in brain aging, genetic risk factors and the effects of sex steroid and other hormones. We continue to perform serial MRI and PET scans for neuroimaging study participants of the Baltimore Longitudinal Study of Aging. Our initial longitudinal MRI investigations demonstrated significant longitudinal gray and white matter tissue loss over a four-year interval even in healthy older adults (Resnick et al., J Neuroscience 2003). Recently, we confirmed and extended these findings over a longer (up to 9-year) follow-up interval (Driscoll et al., Neurology 2009). Furthermore, we demonstrated that a number of brain regions, including the hippocampus and orbital frontal region in addition to whole brain volume generally, showed accelerated tissue loss in individuals with mild cognitive impairment (MCI). We use support vector machine algorithms to develop classifiers for prediction of diagnostic status on an individual person basis. We identified a network of abnormalities that contributed to maximal discrimination between MRI scans of normal and MCI individuals in a sample of individuals matched for important demographic characteristics (Fan et al., Neuroimage 2008). We then applied this approach to the AD patients and controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and used the classifier based on that sample to calculate the Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD) scores for all MRI scans of each individual BLSA participant. We demonstrated that higher SPARE-AD abnormality scores were associated with lower verbal memory performance (Davatzikos et al., Brain 2009) and that abnormality scores increased with age and cognitive impairment. Using the 11-C-PIB PET scan data, we confirmed the experience at other centers that 20-30% of cognitively normal older adults have PIB positive scans, i.e., deposition of brain amyloid. In addition, we investigated whether PIB retention was associated with longitudinal rCBF changes in the preceding years (Sojkova et al., 2008). PIB distribution volume ratios (DVR) of regions of interest were estimated by fitting a reference tissue model to the measured time activity curves (Zhou et al, Neuroimage, 2007). The mean cortical DVR was used to divide participants into high and low PIB retention groups. Both regions of greater longitudinal decrease and greater longitudinal increase in rCBF were observed in association with high PIB. While longitudinal declines may reflect greater decrements in neuronal function in the high PIB group, greater longitudinal increases in rCBF are also observed in those with higher amyloid load and may represent a compensatory attempt to preserve neuronal function in these regions. Approximately half of the neuroimaging study participants are enrolled in the BLSA autopsy program, and the integration of autopsy and imaging findings is an active area of investigation (e.g. Iacono et al 2008). BLSA studies have shown that individuals with AD pathology at autopsy but without antemortem cognitive impairment (Asymptomatic AD) have larger nuclei and nucleoli of the anterior and posterior cingulate and the hippocampus, suggesting either a compensatory or inflammatory process. Ongoing studies investigate the cellular basis of neuroimaging findings, including regional volume loss, to try to better define characteristics that accelerate cognitive impairment as well as those that support the maintenance of cognitive health.